title: Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma.
abstract: The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis.
authors.affiliation: Departments of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Scott R P
authors.initials: SR
authors.lastname: McDonnell
authors.forename: Steven R
authors.initials: SR
authors.lastname: Hwang
authors.forename: Delphine
authors.initials: D
authors.lastname: Rolland
authors.forename: Carlos
authors.initials: C
authors.lastname: Murga-Zamalloa
authors.forename: Venkatesha
authors.initials: V
authors.lastname: Basrur
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Conlon
authors.forename: Damian
authors.initials: D
authors.lastname: Fermin
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolfe
authors.forename: Alexander
authors.initials: A
authors.lastname: Raskind
authors.forename: Chunhai
authors.initials: C
authors.lastname: Ruan
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Jiang
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Charles F
authors.initials: CF
authors.lastname: Burant
authors.forename: Kojo S J
authors.initials: KS
authors.lastname: Elenitoba-Johnson
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D055432:Metabolomics; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D040901:Proteomics; D013379:Substrate Specificity; D013963:Thyroid Hormones / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D008565:Membrane Proteins; D011505:Protein-Tyrosine Kinases; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C107023:p80(NPM-ALK) protein